BSTRACT
A thirteen-year-old, male, castrated, non-azotemic European Shorthair was presented for treatment of hyperthyroidism. Thyroid scintigraphy using Tc99m showed bilaterally enlarged thyroid glands with an increased thyroid to salivary (T/S) ratio. The cat was treated with an intravenous injection of 4.84 mCi (179MBa) 131I. One year later, the cat showed clinical deterio- ration, including lethargy, weight loss and a louder heart murmur; iatrogenic hypothyroidism was diagnosed. Concurrently, renal parameters were elevated compared to the pre-treatment values. Supplementation with levothyroxine was started. Four months later, the cat was euthy-roid and improved creatinine values were noted. In this case report, the diagnosis and manage-ment of iatrogenic hypothyroidism in cats and the interplay with renal function are described. An algorithm with recommendations regarding diagnosis, monitoring and treatment of these cats is presented.
SAMENVATTING
Een mannelijke, gecastreerde, niet-azotemische Europese korthaar van dertien jaar werd aange-boden voor de behandeling van hyperthyroïdie. Schildklierscintigrafie met Tc99m onthulde bilateraal
vergrote schildklieren met een toegenomen “thyroid to salivary (T/S) ratio”. De kat werd behandeld met 4,84mCi (179Mba) 131I. Een jaar later vertoonde de kat klinische achteruitgang, zoals lethargie,
gewichtsverlies en een luidere hartruis; iatrogene hypothyroïdie werd gediagnosticeerd. Tegelijker-tijd waren de nierwaarden gestegen ten opzichte van voor de behandeling. Een levothyroxinetherapie werd opgestart. Vier maanden later was de kat opnieuw euthyroïde en was de serum-creatininewaarde opnieuw gedaald. In deze casuïstiek worden de diagnostiek en het management beschreven van katten met iatrogene hypothyroïdie en het effect van iatrogene hypothyroïdie op de nierfunctie wordt nader toegelicht. Bijkomend wordt een algoritme opgesteld met aanbevelingen voor diagnostiek, monitoring en behandeling van hyperthyroïde katten die behandeld worden met radioactief jodium.
A
INTRODUCTION
Hyperthyroidism is the most common endocrine disorder in elderly cats (Peterson and Ward, 2007). This disease can be treated pharmacologically, surgi-cally, dietary or with radioiodine therapy (Daminet et al., 2014) (Table 1).
Treatment with 131I is considered the gold standard
in many cats as it is curative and safe. The
adminis-Iatrogenic hypothyroidism in a hyperthyroid cat treated with
131I
Iatrogene hypothyroïdie bij een hyperthyroïde kat behandeld met
131I
1N. De Laet, 1L. Stammeleer, 2E. Vandermeulen, 1D. Paepe, 1S. Daminet
1Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133,
9820 Merelbeke, Belgium
2Department of Medical Imaging of Domestic Animals and Orthopedics of Small Animals,
Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium nikita.delaet@ugent.be
tered radioiodine is taken up by the thyroid glands and the emitted β radiation destroys the nearby abnormal thyroid tissue. The remaining thyroid tissue is mostly atrophied, hence will be spared of most of the radia-tion (Daminet et al., 2014; Daminet and Hill, 2017).
131I treatment has a 90-95% success rate (Volckaert et
al., 2016). The major disadvantages of 131I therapy are
the need for a licenced, specialized center, the use of radioactive products, the need for hospitalization and
the possible development of iatrogenic hypothyroid-ism (Table 1).
Iatrogenic hypothyroidism has been reported in 3-79% of all 131I-treated cats, although in most
stud-ies, a prevalence of iatrogenic hypothyroidism of ap-proximately 10% has been shown (Meric and Rubin, 1990; Boag et al., 2007; Lucy et al., 2017; Peterson et al., 2017).
Cats with iatrogenic hypothyroidism rarely show obvious clinical signs. Lethargy, weight gain and an-orexia are the most commonly noted. However, these clinical signs are difficult to recognize by the owner since resolution of hyperthyroidism should lead to improvement of the typical clinical signs of hyper-thyroidism, including hyperactivity, polyphagia and weight loss. The combination of these vague clinical signs and the possible influence of concurrent illness on total thyroxine (TT4) concentrations (euthyroid sick syndrome) makes diagnosing iatrogenic hypo-thyroidism after 131I treatment challenging (Peterson,
2016).
Once iatrogenic hypothyroidism has been diag-nosed, the veterinarian can decide to either start treat-ing the cat with thyroid hormone supplementation or continue monitoring. This decision can be difficult to make and depends on a combination of the presence or absence of clinical signs, the time of diagnosis and the renal values of the cat (Williams et al., 2014).
Once treatment with levothyroxine has been ini-tiated, frequent re-evaluations should take place to
evaluate the clinical response and to measure post-treatment TT4 for therapeutic monitoring. This is important to avoid under- or overdosing of levothy-roxine, with persistent hypothyroidism or iatrogenic hyperthyroidism as a consequence. Therapeutic mon-itoring of total T4 concentrations should take place in every cat treated with levothyroxine, because many factors, including gastrointestinal disease and concur-rent administrations of other medications, influence the absorption of levothyroxine (Daminet, 2016).
In this case report, the recommended protocols of diagnosing, treating and re-evaluating iatrogenic hypothyroid cats after radioiodine treatment are de-scribed.
CASE DESCRIPTION
A thirteen-year-old, male, castrated European Short- hair was presented at the referring veterinarian with chronic weight loss, polyphagia and being quieter. The diagnosis of hyperthyroidism was confirmed based on increased serum TT4 concentration. Treat-ment with methimazole was instituted, and the cat was referred to the Small Animal Clinic of the Faculty of Veterinary Medicine, Ghent University, for further work-up and possibly radioiodine treatment. Blood examination (including free T4 (fT4), TT4, hemato-logy and biochemistry), urinalysis, thoracic X-rays, echocardiography and an abdominal ultrasound were Table 1. Summary of considerations regarding treatment options for feline hyperthyroidism. (Adapted from Daminet, 2019).
Anti-thyroid Restricted Thyroidectomy 131I drugs iodine diet
Initial cost + + +++ +++
Long-term cost ++ ++ + +
Pre-requisites None Strict administration Skilled Licenced facility of this diet needs surgeon
to be possible
Ease of use for the owner Easy to Easy Easy after Radioprotective
moderate hospitalization measures needed,
afterwards easy
Need for anesthesia No No Always Sometimes
Time to euthyroid 2-4 weeks 6-8 weeks 1-2 days Days to weeks
Hospitalization No No 1-3 days 3 days to 4 weeks
Potential limitation Mild side-effects Low palatability Recurrence after Iatrogenic common in some cats unilateral/ hypothyroidism
incomplete or persistent thyroidectomy hyperthyroidism
performed as part of an extensive work-up for a pro-spective study.
Initial physical examination revealed typical clini-cal features of hyperthyroidism including muscle at-rophy, palpation of a goitre and a systolic heart mur-mur (Table 2).
Initial blood examination, including biochemistry, hematology and thyroid profile, confirmed the diag-nosis of hyperthyroidism with severely increased TT4 and fT4 values and a low normal TSH concentration (Table 3).
Urinalysis prior to the 131I treatment revealed
con-centrated urine with mild proteinuria (Table 4). Chest X-rays revealed mild cardiomegaly. Echocardiogra-phy visualized mild hypertroEchocardiogra-phy of the left ventricle with borderline left atrium dilation and dynamic right ventricular outflow tract obstruction (DRVOTO). Ab-dominal ultrasound did not reveal any significant ab-normalities.
Thyroid scintigraphy with Tc-99m showed bilater-al enlarged thyroid glands with an increased tracer up-take (Figure 1). The left thyroid gland was displaced caudally. The thyroid-to-salivary (T/S) ratio was in-creased in both left (10/1) and right (3.9/1) thyroid glands.
The results obtained from bloodwork and pertech-netate scan in this cat were consistent with the con-firmed hyperthyroidism. Treatment with an intrave-nous injection of 4.84mCi (179MBq) 131I was
institut-ed. This dose was based on the T/S ratio obtained via scintigraphy, TT4 value and clinical signs (Volckaert et al., 2016). The cat was hospitalized for five days due to radioprotective precautions.
One month post-treatment control included uri-nalysis, abdominal ultrasound and echocardiography. Significant clinical improvement was noticed (Table 2). Bloodwork revealed TT4 and fT4 serum concen-trations that had dropped below the reference interval and serum TSH concentration well within the upper range of the reference interval. The serum creatinine and urea concentrations were still within reference in-terval, but had significantly increased compared to the pre-treatment serum concentrations (Table 3). Urinaly- sis revealed decreased urine concentration compared to the baseline values (Table 4).
The patient returned for a control visit one year after treatment. Blood and urine examinations, scinti-graphy, abdominal ultrasound and echocardiography were performed. Significant clinical deterioration in-cluding weight loss, mild muscle wastage and a loud-er heart murmur was noticed and the cat had become significantly more quiet at home (Table 2). The patient was also hypertensive with a mean blood pressure of 205mmHg (measured with Doppler ultrasonography).
Control bloodwork showed low normal serum TT4 and decreased serum fT4 values, combined with a high serum TSH concentration (Table 3). Concur-rent renal disease was also suspected based on an in-crease in serum values of SDMA, urea and creatinine compared to pre-treatment and significant proteinuria (Tables 3 and 4). The rest of the performed blood-work, including full hematology, biochemistry and electrolytes, was unremarkable.
Both thyroid glands could no longer be clearly Figure 1. Pertechnetate scan in a hyperthyroid cat prior
to 131I treatment.
Table 2. Findings on physical examination in a hyperthyroid cat prior to 131I, and at one and twelve months later (T0, T1 and T12, respectively).
T0 T1 T12 Muscle condition score Moderate muscle atrophy No muscle atrophy Mild muscle atrophy
Weight (kg) 2.8 3.6 3.02
Thyroid gland palpation* 5/6 L - 0/6 R 4/6 L - 0/6 R 0/6 L – 0/6 R
Body condition score (BCS) 4/9 5/9 4/9
Heart murmur 3/6 1-2/6 3/6
*Thyroid gland scoring system: score 0 = non-palpable thyroid gland; score 1 =1-3 mm; score 2 = 3-5 mm; score 3 = 5-8 mm; score 4 = 8-12mm; score 5 = 12-25mm and score 6 = ≥25 mm (Boretti et al., 2005; Paepe et al., 2008).
delineated due to decreased radionuclide uptake on thyroid scintigraphy (Figure 2). The T/S ratio was es-timated to be 0.78/1, but was hard to determine due to the limited visibility of the thyroid glands on scin-tigraphy.
Based on the low normal TT4, low fT4, increased TSH concentration and decreased radionuclide uptake on scintigraphy, this cat was diagnosed with iatroge-nic hypothyroidism one year after 131I treatment.
Echocardiography showed a mild, focal thicken-ing of the septum with very mild dilation of the left atrium. These findings did not have any clinically relevance at that time point. Abdominal ultrasound didn’t show any significant abnormalities.
Supplementation with levothyroxine (Leventa MSD animal health, United Kingdom; 0,075ml = 0.075mg twice daily) was prescribed.
Control bloodwork was performed four months after the initiation of thyroxine supplementation. The serum TT4 concentration was within normal limits and the urea and creatinine values were mildly de-creased. The cat had improved clinically. However, the serum SDMA concentrations were further in-creased (Table 3).
DISCUSSION
Although radioiodine treatment is the preferred treatment option for hyperthyroidism, in some cats, it also involves disadvantages and complications. One of the main complications is the potential develop-ment of iatrogenic hypothyroidism (Meric and Rubin,
1990; Boag et al., 2007; Lucy et al., 2017; Peterson et al. 2017).
One of the predisposing factors for 131I therapy
in-duced iatrogenic hypothyroidism is the usage of (too) high doses of radioiodine. The standard dose for treat-ing hyperthyroidism in cats with 131I used to be
ap-proximately 4-5 mCi, but recently, it has been shown that with a dose of 2mCi, most cats with mild-to- moderate hyperthyroidism without an increased fre-quency of persistent hyperthyroidism three and six Figure 2. Pertechnetate scan in an iatrogenic hypo-thyroid cat, twelve months after 131I treatment to treat hyperthyroidism.
Table 3. Findings on serum biochemistry in a hyperthyroid cat prior to 131I, and at one, twelve and sixteen months after treatment (T0, T1, T12 and T16, respectively).
Results Results Results Results Reference
T0 T1 T12 T16 interval
Total T4 >167.3 9 15.4 33.54 10-60 nmol/l
Free T4 (Immulite) 77.2 4.5 4.2 9.0-33.5 pmol/l
Free T4 (Equilibrium dialysis) 108.7 5 11.2 9.0-33.5 pmol/l
TSH 0.03 0.11 0.58 0.03-0.3 ng/ml * Urea 6.2 11.7 12.4 10.16 5.7-13.5 nmol/l Creatinine 48 103 123 106.1 <168 µmol/l SDMA 9 9 17 20 0-14 µg/dl Bilirubin 1.7 2,7 2.7 <6.8 µmol/l ALT 277 150 129 <175 U/l ALP 155 46 36 <73 U/l GGT <1 1 1 <5 U/l AST 131 60 48 <71 U/l
Total Calcium 2.3 2.5 2.3 2,2-2,9 mmol/L
Total Protein 59 78 59-87 g/l
Albumin 25 30 27-44 g/l
Globulin 34 48 29-54 g/l
SDMA = Symmetric dimethylarginine; ALT = Alanine aminotransferase; ALP = Alkaline phosphatase; GGT = gamma glutamyl transferase; AST = aspartate aminotransferase
months post therapy can be successfully treated (Lucy et al., 2017). Although the dosage currently used in the clinic at the Faculty of Veterinary Medicine (Ghent University) has been adapted to 2mCi, the cat in the present case, treated in November 2016, still received 4.84 mCi 131I, which is nowadays considered to be a
high dose. Another predisposing factor for iatrogenic hypothyroidism is the presence of bilateral 131I uptake
on thyroid scintigraphy. These cats, including the cat in the present case report, are twice as likely to deve-lop iatrogenic hypothyroidism compared to cats with only unilateral thyroid pertechnetate uptake (Nykamp et al., 2005).
Follow-up of the clinical status and bloodwork af-ter radioiodine treatment is of great importance to be able to make an early diagnosis of iatrogenic hypothy-roidism. However, a complete work-up for iatrogenic hypothyroidism in non-azotemic cats is not recom-mended until three to six months post-treatment, be-cause cats treated with 131I can become transient
hypo-thyroid. These cats regain a normal thyroid function within three to six months after treatment (Peterson et al., 2017). Considering that the cat in the present case was hypothyroid one year post-treatment, chanc-es were very low that he would become spontane-ously euthyroid again. Azotemic cats that have been treated with 131I, should be monitored more closely,
because treatment for hyperthyroidism, development of iatrogenic hypothyroidism and potential concurrent CKD all decrease the glomerular filtration rate (GFR). Iatrogenic hypothyroidism should be diagnosed and treated as early as possible, since it improves renal function and provides a longer median survival time in these cats (Williams et al., 2014; Peterson et al., 2017).
The diagnosis of iatrogenic hypothyroidism is cur-rently based on the measurement of serum TT4 and TSH concentrations. Elderly, euthyroid cats often have low TT4 concentrations due to concurrent non-thyroid illnesses (Peterson, 2016). Free T4 concen-trations are less influenced by non-thyroidal illness and are therefore considered to be more sensitive for diagnosing iatrogenic hypothyroidism. However, the assays available for the measurement of fT4 concen-trations have a variable performance and accuracy. Determining fT4 after equilibrium dialysis (FT4ED) is considered the gold standard. However, FT4ED is an expensive and time-consuming test that is not widely available. In a recent study by Stammeleer et
al. (2018), the measurement of fT4 via a chemilumi-niscent enzyme immunoassay (FT4CEIA) has shown correlating, but consistently lower results compared to FT4ED. However, approximately 75% of iatrogen-ic hypothyroid cats have fT4 values within reference interval (Peterson et al., 2017). Therefore, it is recom-mended to interpret serum TT4 results in combina-tion with serum TSH concentracombina-tions (Peterson et al., 2017).
Currently, there is no feline TSH assay available. The immulite canine TSH assay (Diagnostic Products Corporation, DPC), a chemiluminescent immuno- metric assay, is being used to determine TSH concen-trations in cats because of the cross-reaction of this assay with feline TSH. Multiple studies have been performed to determine a reference interval (RI) for TSH in healthy, elderly cats. The suggested up-per reference limit of feline TSH determined by the cTSH assay varies between 0.15 ng/ml and 0.3 ng/ml (Wakeling, 2010; Williams et al., 2010; Lucy et al., 2017). However, the choice between these two cut-off values will have a major influence on the amount of iatrogenic hypothyroid cats that will be diagnosed after 131I treatment. This emphasizes the need of
fur-ther studies to determine the most appropriate cut-off value for this assay in order to be able to diagnose iatrogenic hypothyroidism in cats. In addition, a re-cent study from Stammeleer et al. (2019) showed that approximately 27% of cats with high cTSH concen-trations are euthyroid based on scintigraphy. In that study, TT4 concentrations were within the reference interval in all of these euthyroid cats with increased cTSH concentrations, which shows us the need to in-terpret TT4 and TSH concentrations together and with caution.
A TSH stimulation test using recombinant human TSH (rhTSH) can also be used to assess the thyroid function. Serum samples should be collected before and 6 hours after IV administration of the exogenous rhTSH. A study by Van Hoek et al. (2010) showed that iatrogenic hypothyroid cats do not show a significant increase in TT4 after the administration of rhTSH, in contrast to healthy cats or cats with non-thyroid ill-ness. One of the main disadvantages of this test is the high cost for a vial of rhTSH. However, once opened, these vials can be stored for four to eight weeks with-out any loss of biological activity, making it possible to perform multiple TSH stimulation tests with one vial (De Roover et al., 2006).
Table 4. Findings on urinalysis in a hyperthyroid cat prior to 131I, and at one and twelve months after treatment (T0, T1 and T12, respectively).
Result T0 Result T1 Result T12 Reference interval
Specific gravity >1.050 1.015 1.020
UPC 0.6 0.2 2.9 0-0.4
Thyroid scintigraphy is considered the best imag-ing modality to diagnose iatrogenic hypothyroidism in cats that had received radioiodine treatment. Cats with true iatrogenic hypothyroidism show decreased or absent radionuclide uptake on scintigraphy, where-as cats with low T4 concentrations due to non-thyroi-dal illness have a normal radionuclide uptake (Peter-son, 2013). However, cats that become hypothyroid after methimazole treatment should not be diagnosed with scintigraphy since methimazole can potentially increase the radionuclide uptake, causing a falsely increased T/S ratio (Peterson and Broome, 2015). Unfortunately, thyroid scintigraphy is currently not routinely available for most veterinarians (Peterson, 2013).
Whether or not iatrogenic hypothyroidism should be treated immediately or monitored depends on the renal function of the cat. When bloodwork does not reveal azotemia, the iatrogenic hypothyroidism should not be treated within the first six months after
131I treatment. However, if the cat is azotemic,
treat-ment with thyroid hormone suppletreat-mentation has been shown to improve renal function and increase the median survival time in these cases (Williams et al., 2014; Vaske et al., 2015; Peterson et al, 2017). An al-gorithm with recommendations regarding diagnosis, monitoring and treatment of hyperthyroid cats treated with 131I is presented in Figure 3.
Unfortunately, currently, there is no reliable test available that predicts post-treatment azotemia in hyperthyroid cats. Serum creatinine (sCr) concentra-tions are influenced by body muscle mass, which is usually decreased in hyperthyroid cats. Increased glo-merular filtration rate (GFR) in hyperthyroid cats also leads to decreased sCr concentrations, which makes it a less optimal indicator for azotemia in these cats. Direct measurement of GFR is not frequently used in clinical settings because the process is time-de-manding and potentially stressful for the cats. Serum symmetric dimethylarginine (SDMA), a byproduct of cellular protein metabolism, is not affected by these extrarenal factors and is therefore suspected to be a better biomarker for the detection of CKD. However, SDMA has a poor sensitivity (33%) to diagnose early kidney disease in hyperthyroid cats (Peterson et al., 2018). In addition, Burresova et al. (2019) showed that cats treated with 131I show a poor correlation
be-tween SDMA and GFR.
One month post treatment, the cat in the present case already showed decreased TT4 concentrations with normal TSH concentrations. Treatment with L-thyroxine was not instituted at this point in time be-cause 1. only a short period had elapsed after treat-ment, which could reflect transient hypothyroidism; 2. the kidney values remained within the reference interval; 3. no obvious clinical signs of hypothyroi-Figure 3. Algorithm with recommendations regarding the diagnosis, monitoring and treatment for cats treated with 131I (Adapted from Daminet S., 2016).
dism were observed and 4. TSH was not significantly increased.
One year post treatment, the patient was orally ad-ministered levothyroxine because of low serum fT4 concentrations, high serum TSH concentration, de-creased thyroid visibility on thyroid scintigraphy, in-creasing kidney values (still within reference interval) and hypertension. At that time point, the cat became lethargic and had mild weight loss (but still a normal body condition score). Lethargy is a common clinical sign in cats with iatrogenic hypothyroidism. Weight loss, however, is unfrequently noticed in hypothyroid cats (Peterson, 2013). Further diagnostic tests were performed in the cat of the present case, including an extensive blood examination, urinalysis, abdominal ultrasound and echocardiography, which didn’t reveal other abnormalities besides the mild increase in renal values, proteinuria and hypertension. For this reason, it was recommended to closely follow-up these renal parameters after the initiation of treatment with oral levothyroxine. In addition, the cat showed significant clinical improvement once this treatment was started. In the present case, the thyroxine and TSH concen-trations had not been monitored for six months after treatment, due to a loss of follow-up at that time; other- wise, treatment in this cat might have been initiated sooner.
After starting levothyroxine supplementation, im- provement of the mental status and activity level should be noticed within a couple of days. After a couple of weeks, weight loss might be noticed and the hair coat should improve within the first few months. Blood examination should be performed four to eight weeks after the start of the treatment and should in-clude serum urea, creatinine, T4 (TT4 or fT4) and TSH concentrations. Post-treatment blood samples should be collected approximately four hours after the levothyroxine supplementation in order to be able to measure T4 peak serum concentrations. Ideally, T4 concentrations rise and TSH concentrations drop into the reference interval. If these values are not reached, dose adjustment is advised (Daminet, 2016). In the present case, the TT4 concentration increased into the reference interval, renal variables decreased and the cat was clinically stable, hence no dose adjustment was instituted. The serum SDMA concentration in the present case was higher than one year after the 131I
treatment. There are currently no studies available in which the correlation of sSDMA and GFR has been examined in iatrogenic hypothyroid cats treated with levothyroxine, which makes the interpretation of this result challenging.
It is important to note that also medical treatment with methimazole can cause iatrogenic hypothyroid-ism in cats. Between 20 - 40% of cats treated with me-thimazole become iatrogenic hypothyroid (Aldridge et al., 2015). Many of these cats have TSH concentra-tions within the reference interval during the first three months of treatment, but iatrogenic hypothyroidism
often occurs at a later stage of treatment (Aldridge et al., 2015). Just as in cats treated with 131I, TT4 or fT4
values should always be interpreted in combination with TSH concentrations. This emphasizes the impor-tance of closely monitoring these cats, including regu-lar bloodwork to check T4 and TSH concentrations in cats treated with methimazole. When low/normal low T4 concentrations and high TSH concentrations are found, the methimazole dose should be lowered, even in the absence of clear clinical signs (Aldridge et al., 2015).
CONCLUSION
Diagnosing, monitoring and treating iatrogenic hypothyroidism in cats can be challenging. Making the decision to start thyroid hormone supplementation can be difficult as iatrogenic hypothyroidism can be transient. Currently, thyroid hormone supplementa-tion is always recommended in azotemic cats as iatro-genic hypothyroidism could negatively influence sur-vival rates in these cats (Figure 3).
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